Disorders of sex development in Wolf–Hirschhorn syndrome: a genotype–phenotype correlation and MSX1 as candidate gene

Abstract

Background Wolf–Hirschhorn (WHS) is a set of congenital physical anomalies and mental retardation associated with a partial deletion of the short arm of chromosome 4. To establish a genotype–phenotype correlation; we carried out a molecular cytogenetic analysis on two Tunisian WHS patients. Patient 1 was a boy of 1-year-old, presented a typical WHS phenotype while patient 2, is a boy of 2 days presented an hypospadias, a micropenis and a cryptorchidie in addition to the typical WHS phenotype. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used. Results Results of the analysis showed that patient 2 had a greater deletion size (4.8 Mb) of chromosome 4 than patient 1 (3.4 Mb). Here, we notice that the larger the deletion, the more genes are likely to be involved, and the more severe the phenotype is likely to be. If we analyze the uncommon deleted region between patient1 and patient 2 we found that the Muscle Segment Homeobox (MSX1) gene is included in this region. MSX1 is a critical transcriptional repressor factor, expressed in the ventral side of the developing anterior pituitary and implicated in gonadotrope differentiation. Msx1 acts as a negative regulatory pituitary development by repressing the gonadotropin releasing hormone (GnRH) genes during embryogenesis. We hypothesized that the deletion of MSX1 in our patient may deregulate the androgen synthesis. Conclusion Based on the MSX1 gene function, its absence might be indirectly responsible for the hypospadias phenotype by contributing to the spatiotemporal regulation of GnRH transcription during development.

Genome-Wide Association of New-Onset Hypertension According to Renin Concentration: The Korean Genome and Epidemiology Cohort Study

“…It also plays roles in the limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with non-syndromic cleft lip, with or without cleft palate, Witkop syndrome, Wolf-Hirschhorn syndrome, and autosomal dominant hypodontia [45][46][47][48]. The second SNP (rs8137145) showed a p-value of 6.4 × 10 −6 , suggesting an association with protection against hypertension.…”

Anomalies in Human Sex Determination: Usefulness of a Combined Cytogenetic Approach to Characterize an Additional Case with Xp Functional Disomy Associated with 46,XY Gonadal Dysgenesis

“…CGH 4x44K micro-array was performed using the agilent platform as previously described ( 11 , 12 ). Agilent ® oligonucleotide array was performed according to the manufacturer’s instructions (Agilent Human Genome CGH Microarray kit 44K ® ).…”

A Familial Chromosome 4p16.3 Terminal Microdeletion That Does Not Cause Wolf-Hirschhorn (4p-) syndrome

“…Deletion of the LETM1 gene appears to be associated with WHS-associated seizure disorder ( 14), (15), however haploinsu ciency of LETM1 independently appears insu cient in epileptogenesis and seizure genesis (16). There is growing evidence that loss of the MSX1 gene [(OMIM 142983) located proximal to 4p16.3, on 4p16.2] may be responsible for the dental abnormalities as well as cleft lip and/or palate that can be seen in WHS (17), (18). The potential role(s) of other genes around the 4p16.3 region are subjects of ongoing investigations.…”